Early-Onset Neonatal Sepsis: Clinical System Involvement and Maternal–Neonatal Risk Profiles in a Retrospective Cohort Study

Background/Objectives: Neonatal sepsis remains a major contributor to neonatal morbidity and mortality worldwide, yet diagnostic uncertainty and heterogeneous clinical presentation continue to challenge early recognition and management. Early-onset sepsis (EOS), typically arising within the first 72 h of life, is strongly influenced by maternal and perinatal factors. Limited data exist on the temporal evolution of clinical system involvement during the first week of life. This study aimed to identify the predominant clinical systems involved in preterm and term neonates with suspected or confirmed sepsis and to determine maternal and neonatal risk factors associated with early disease severity, persistent sepsis, and adverse outcomes. Methods: A total of 297 neonates met the inclusion criteria. Most infants (99.3%) were admitted before 72 h of life. Clinical system involvement was recorded daily, and maternal–neonatal risk factors were analyzed to identify predictors of advanced sepsis at presentation, persistent sepsis at Day 7, and mortality. Results: Respiratory involvement was the predominant clinical system affected on Day 1 (57.2%) and remained common through Day 3. CNS, gastrointestinal, and skin involvement were infrequent. Lower gestational age (p = 0.035) and prolonged rupture of membranes >18 h (p = 0.043) independently predicted sepsis at Day 1. Advanced sepsis at admission was associated with lower birth weight, lower gestational age, older maternal age, and absence of intrapartum antibiotics (all p ≤ 0.001). Persistent sepsis at Day 7 was linked to prematurity (p = 0.008), higher mortality (p < 0.001), and prolonged hospitalization (p = 0.001). Conclusions: Respiratory involvement was the most common clinical system affected in neonates with EOS. Prematurity, low birth weight, prolonged rupture of membranes, and maternal intrapartum infection significantly increased the risk of severe disease. Understanding the evolution of clinical system involvement during the first days of life may support more precise risk stratification and reduce unnecessary antibiotic exposure.